EE3018 Introduction to Photonics

Laser Technology for Medical Applications

- Photodynamic Therapy

Goh Cai Yu

Professor: Wang Qijie

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Table of Content

1. Motivation for this research topic.........................................................................................3

2. Introduction of Laser and Photodynamic Therapy................................................................3
2.1 Introduction of Lasers in the Medical Field….....................................................................3
2.2 Introduction of Photodynamic therapy................................................................................3
2.3 The Scientific Concept and Working Principle of Photodynamic therapy...........................3
2.3.1 Laser-tissue interactions ……….....................................................................................3
2.3.2 Photosensitizers………………………………………………………………………………..4
2.3.3 Photodynamic Therapy………………………………………………………………………..5
3. The development of Photodynamic Therapy throughout the years.....................................6
3.1 Past State of Photodynamic Therapy.................................................................................6
3.2 Present State of Photodynamic Therapy............................................................................6
3.3 Future State of Photodynamic Therapy..............................................................................6
4. Application of Photodynamic Therapy - Lung Cancer Treatment.........................................7
4.1 Laser-tissue interaction for Photodynamic Therapy...........................................................7
4.2 Lung Cancer Therapy Using Photodynamic Therapy........................................................7
5. Limitations of Photodynamic Therapy..................................................................................8
6. Discussion of PDT and my opinion…………………………….............................................9
7. Conclusion...........................................................................................................................9
8. Reference...........................................................................................................................10

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1. Motivation for this research topic

With the improvement of medical procedures, therapies such as radiation therapy and
chemotherapy are now considered ineffective due to its adverse side effects.
This led to the development of laser therapy which is less invasive, no known side effects
and results in minimal scarring. (done)

The motivation for this research topic is to learn more about laser technology for medical
applications. Through this literature review, I gained a deeper understanding on the
importance of laser technology such as photodynamics therapy in the medical field, as well
as the scientific concepts behind photodynamics therapy. (done)

2. Introduction of Laser and Photodynamic Therapy

2.1 Introduction of Lasers in the Medical Field

Lasers have been used in a multitude of medical procedures such as cancer and wound
treatment, dentistry, dermatology and cosmetic surgery, and nerve stimulation. Lasers have
the ability to concentrate precisely on small areas, hence less damage is done to
surrounding tissue. This reduces pain, swelling, and scarring as compared to traditional
surgery. (done)

2.2 Introduction of Photodynamic therapy

Photodynamic therapy (PDT) eradicates target cells by utilising reactive oxygen species
(ROS). These ROS are created by irradiating photosensitizing agents with light of suitable
wavelength. Some benefits of PDT include eradicating bacteria quickly, slim chance of
developing a resistance to PDT and ensuring the safety of tissues. PDT is employed in a
variety of medical applications such as dentistry, cancer treatment and dermatology. (done)

2.3 The Scientific Concept and Working Principle of Photodynamic Therapy

2.3.1 Laser-tissue Interactions

When a laser is irradiated on tissue, the laser can be reflected, absorbed, scattered,
transmitted through the tissue or have interactions with the tissue. Laser-tissue interactions
are dependent on the tissue’s physical properties and laser parameters. These laser
parameters consist of wavelength, energy, intensity, pulse-width, repetition rate and the
operating modes such as pulsed mode or continuous wave mode. (done)

In the biomedical industry, lasers are involved in 5 interaction mechanisms. (done)

These interaction mechanisms are
1) purely optical (done)
2) photochemical (produce light-induced chemical reactions by targeting cells)
e.g. PDT (done)
3) photoablative (breaking of tissue’s molecular bonds or photodissociation) (done)

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4) photothermal (transforms energy from light into heat energy, leading the tissue to rise in
temperature and evaporate) (done)
5) photomechanical (expansion of shock wave plasma causes localised mechanical rupture,
resulting in dielectric breakdown in tissue) (done)

Fig 1. Graphical representation irradiance against exposure time (done)

Laser exposure duration and amount of irradiation affects the type of laser-tissue
interactions. Fig 1 shows how laser exposure duration and amount of irradiation is related to
the type of laser-tissue interactions. (done)

2.3.2 Photosensitizers

Photosensitizers (PS) in PDT are compounds which enable light energy to be transferred
and converted into a type II chemical reaction. Longer activation wavelength of PSs allows
further light penetration. Currently, the majority of PSs are triggered by red light with
wavelengths ranging from 630-700 nm. (done)

Table 1 : Types of PSs Table 2 : Generations of PSs

2.3.3 Photodynamic Therapy

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 Fig 3. Photodynamic Therapy’s Mechanism

Fig 3 shows the mechanism behind PDT. Firstly, light is illuminated on PS in ground singlet
state (PS). Absorption of photons excites PS to a singlet excited state (PS*). The PS* state
is very short-lived and unstable, hence it can de-excite back PS by getting rid of energy
through emitting light (fluorescence).(done)

Via intersystem crossing, PS* can be converted to a long-lived and stable state, the triplet
excited state (PS*-). Intersystem crossing is achieved through spin conversion of the
electron in the higher-energy orbital. PS*- can revert to PS by emitting light
(phosphorescence). PS*- can also perform type I or II reactions. (done)

For Type I reaction, PS* directly reacts with a substrate. Some examples of substrates are
cell membranes or molecules. Next, a hydrogen atom may be removed or an electron may
be transferred, to produce free radicals and radical ions. molecular oxygen(O2) interacts with
these radicals, creating ROS. (done) For Type II reaction, since PS*- is a long lived state,
there is enough time for direct transfer of energy to O2, leading to the creation of singlet
oxygen(1O2) which is a type of ROS. (done)

These 2 reactions can occur together. The ratio between the occurrence of type I and II
reactions are determined by the substrate, PS, oxygen concentration, and binding affinity
between the substrate and PS. However, during PDT type II reaction is more dominant.
(done)

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3. The development of Photodynamic Therapy throughout the years

In the 1900’s, the first application of PDT was made known. Raab demonstrated the
dependence of light and the concept that only certain wavelengths of light can be absorbed
by the sensitising “dye”. (done)

Von Tappeiner later referred to this photosensitization phenomenon as photodynamic. He

applied eosin to basal cell carcinomas topically, then illuminated visible light to it. It was
shown that dynamic interaction between oxygen, light and photosensitizing agents was able
to destroy target tissues. In 1995, FDA approved HpD, also known as Photofrin, as a clinical
application of PDT. (done)

3.1 Past State of Photodynamic Therapy

In the past, PDT was utilised for skin diseases for example psychosis and actinic keratosis.
Initially, first generation PSs were used. However, first generation PSs had molecular and
cellular limitations. For example, low absorption at red wavelengths, hence only a small
amount of light could enter the skin. A large majority of light was blocked on the skin surface,
hence causing cutaneous photosensitive toxicity. In addition, there were problems such as
high hydrophobicity, cytotoxicity, and phototoxicity. (done)

The chemical structure of the first generation PSs were adjusted to improve organelle
targeting and deeper light penetration. This led to the invention of second-generation PSs.
(done)

3.2 Present State of Photodynamic Therapy

During chemical modifications for active and passive targeting, the third-generation of PSs
were discovered. It has the capability to be used with delivery moieties that can stick
nanoparticles or liposomes. (done)

However, PDT still faces many challenges such as insufficiency of light dosimetry and
non-ideal PS properties. Hence, leading to the creation of combination therapy of PDTs with
chemotherapy, Radiation Therapy, immunotherapy and anti-angiogenesis therapy and
hypothermia [5]. Currently, PDT is used for cancers such as lung and brain cancer and
non-cancerous conditions like gastritis and acute sinusitis. (done)

3.3 Future State of Photodynamic Therapy

There may be future development of PSs to achieve a more ideal PS. This allows for more
accurate targeting hence less damaging to surrounding tissue which can reduce swelling,
irritation and pain from PDT. (done)

There may be new inventions of delivery systems to the skin other than nanotechnologies or
liposomes. However, it will be challenging to accumulate tissues in the sensitizer faster and
more selectively. (done)

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4. Application of Photodynamic Therapy - Lung Cancer Treatment

In Singapore, 1 out of 3 people will be diagnosed with cancer, and 1 out of 4 deaths are
caused by cancer. From 2015-2019, lung cancer took up 13.7% of cancer cases for males
and 7.7% of cancer cases for females. (done)

4.1 Laser-tissue interaction for Photodynamic Therapy

Fig 1. tissue penetration depth (d) (done)

Fig 2. Coupling Equations for PDT (done)

Fig 1 shows the depth of tissue penetration (d) of different lasers is dependent on
wavelength and the depth of tissue penetration equation. Fig 2 shows the equations
governing the concentration for PS and intensity of light for laser-tissue interaction for PDT.
(done)

4.2 Lung Cancer Therapy Using Photodynamic Therapy

Firstly, PS is injected into the patient, PS then accumulates in the tumour. The PS is
triggered by light of a suitable wavelength, hence producing ROS. ROS then damages the
cancer cell and its components, causing cancer cell's death through necrosis, apoptosis,
necroptosis, or autophagy. (done)

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 Fig 4. Process of Cancer Cell Death through PDT

5. Limitations of Photodynamic Therapy

- Pain from treatment sessions

Studies discovered that as the intensity of light increases, the level of pain felt by patients
increases as well. To balance a tolerable amount of pain and optimal effectiveness of
treatments is still an obstacle. Hence, scientists may need to investigate using other types of
light sources for photodynamic therapy to reduce the pain of treatment sessions. (done)

- Limit to depth of light penetration

Longer activation wavelength of PSs allows further light penetration. Further research is
required to increase the activation wavelength of PSs so as to enable deeper light
penetration, to allow better and new types of treatment methods. (done)

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6. Discussion of Photodynamic Therapy and my opinion

PDT has many advantages over other medical treatments such as no known long-term side
effects, repeated administration of PDT is safe, non-invasive and more accurate than some
treatments like surgery, with little to no scarring. Although PDT is a better treatment method
as compared to some other treatment methods, PDT still has some side effects such as
pain, swelling, irritation, skin discoloration or infections, after treatment. (done)

As an engineer, I believe we should always strive to maximise efficiency and accuracy of

processes. Further development of PS may lead to the creation of a fourth-generation of
PSs with more accurate targeting which can minimise damage done to surrounding tissue,
reducing pain, swelling and irritation. Deeper research on new carrier moieties may create
faster delivery systems. This can reduce the time taken for PDT treatment. (done)

7. Conclusion

PDT is making good progress in the treatment of cancer and many other diseases which are
drug resistant and overcome the patient’s immune system. In the near future, PDT could
possibly be spearheading cancer diagnosis and treatment. The challenges faced by PDT
require further development of PSs, exploring other light sources and investigating new
delivery moieties. (done)

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8. References

[1] Rodrick Symon Katete, Given Kalonga, Magdah Ganashi, Ned Silavwe, Richard Mwenya,
Photodynamic Therapy for the Diagnosis and Treatment of Cancer, Advances in
Biochemistry. Volume 10, Issue 3, September 2022 , pp. 81-93. doi:
10.11648/j.ab.20221003.11 (done)

[2] Lin JT (2016) Progress of medical lasers: Fundamentals and applications Med Devices
Diagn Eng 2: doi: 10.15761/MDDE.1000111 (done)

[3] Y. N. Chaveset al., “Pain in photodynamic therapy: mechanism of action and

management strategies,” An. Bras. Dermatol., 87 (4), 521 –529 (2012).
http://dx.doi.org/10.1590/S0365-05962012000400001 0365-0596 (done)

[4] Razvigor Darlenski, Joachim W. Fluhr, "Photodynamic therapy in dermatology: past,

present, and future," J. Biomed. Opt. 18(6) 061208 (13 November 2012)
https://doi.org/10.1117/1.JBO.18.6.061208 (done)

[5] Mahmoud H. Abdel-kader, CHAPTER 1:The Journey of PDT Throughout History: PDT
from Pharos to Present , in Photodynamic Medicine: From Bench to Clinic, 2016, pp. 1-21
DOI: 10.1039/9781782626824-00001 (done)

[6] M. Gallardo-Villagrán, D. Y. Leger, B. Liagre, and B. Therrien, “Photosensitizers Used in

the Photodynamic Therapy of Rheumatoid Arthritis,” International Journal of Molecular
Sciences, vol. 20, no. 13, p. 3339, Jul. 2019, doi: 10.3390/ijms20133339. (done)

[7] Dave D, Desai U, Despande N. “Photodynamic Therapy: A View through Light,” J Orofac
Res 2012;2(2):82-86 (done)

[8] Ludmil B. “Photodynamic Therapy: Current Status and Future Directions,” Med Princ
Pract 2015, vol. 24(suppl 1), p. 14–28, May. 2014, doi: 10.1159/000362416 (done)

[9] Gunaydin G, Gedik ME and Ayan S (2021) Photodynamic Therapy—Current Limitations

and Novel Approaches. Front. Chem. 9:691697. doi: 10.3389/fchem.2021.691697 (done)

[10] Kessel D. Photodynamic Therapy: A Brief History. J Clin Med. 2019 Oct 2;8(10):1581.
doi: 10.3390/jcm8101581. PMID: 31581613; PMCID: PMC6832404. (done)

[11] Correia,J.H.; Rodrigues, J.A.; Pimenta, S.; Dong, T.; Yang, Z. Photodynamic Therapy
Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics
2021,13,1332. https://doi.org/10.3390/pharmaceutics13091332(done)

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